Traumatic brain injury (TBI) is the most common type of acquired brain injury in both children and adults. To date, most of our insight into the pathology and treatment of TBI has focused on the regional physiology that occurs following trauma. Our knowledge about what happens at the cellular and molecular level following such injuries, however, is limited. Recently, endogenous neural stem cells have been implicated in the cellular remodeling that occurs following various types of brain injury. We recently demonstrated, using a mouse model of TBI, that neural stem cells proliferate, migrate to, and help remodel injured areas of the brain. It is still unclear, however, how much neural stem cells contribute to this remodeling and whether this contribution occurs in a functionally useful way. This proposal will focus on molecularly modeling TBI in the mouse hippocampus in order to determine the role of endogenous neural stem cells on hippocampal recovery after injury. In Specific Aim 1, we will quantify the magnitude and time course of stem cell proliferation in the hippocampus following TBI. We will do this using a transgenic animal that we have developed and characterized that expresses GFP exclusively in adult neural progenitor cells. In Specific Aim 2, we will determine whether functional recovery following TBI depends on hippocampal stem cell proliferation. We will do this using gain- and loss-of-function studies with mouse genetic models that we have recently developed. These include the nestin-rtTA-GFP mouse referenced above as well a Bax- deficient mouse that is neuroprotected following injury and has an abundance of neural stem cells. Finally, in Specific Aim 3, we will determine how intracellular calcium affects the survival of hippocampal neural stem cells. We will do this ex-vivo using organotypic hippocampal cultures and by measuring in individual neural stem cells how calcium flux is affected by cellular regulators such as the IP3 receptor. Acquired brain injuries, such as those resulting from trauma, are among the most common causes death and long-term disability in all age groups. It is unclear whether neural stem cells are responsible for some of the limited recovery that spontaneously occurs following such injuries. In this proposal, we will not only define the role that stem cells play in recovery following traumatic brain injury, but also identify how these cells might be manipulated to improve recovery after injury.